Abstract Septicemia poses a major health care challenge. Modern therapies requiring suppression of patients' immune systems, a growing numbers of elderly people in the population, and the emergence of drug-resistant bacteria, have increased the prevalence and severity of the disease over the past few decades. Current treatments rely on drugs that do not significant reduce morbidity and mortality. We have discovered that the E3 ubiquitin ligase Cblb can be administered to mice to dramatically curb acute systemic inflammation and lung inflammatory injury in response to the endotoxin of Gram-negative bacteria. We have also delineated the fundamental signaling pathways at which Cblb acts in human cells and showed that its therapeutic benefit is dependent on its E ligase activity. Thus, we now have the knowledge to exploit the therapeutic potential of Cblb as a drug. CellBiologics Inc. proposes to utilize a novel anti-inflammatory cell signaling pathway, i.e., a potential therapeutic human protein, Cblb, that can dramatically improve the outcome of clinical syndromes associated with septicemia. The STTR will help the Company develop small molecules (SMs) that reproduce the intrinsic therapeutic anti-inflammatory action of Cblb and obtain the necessary proof-of-concept data for the development of molecular probes that can be tested in relevant animal models of sepsis. The studies will be done conjointly in the facilities of CellBiologics Inc. and of the University of Illinois in Chicago (UIC). Our long term goal is to produce and test an effective and safe drug for the treatment of sepsis based on the therapeutic efficacy of Cblb described by us and reflected in a recently issued patent (CBLB for treating endotoxin- mediated disorders,US patent No. 8,168,176). Generating molecular probes based on Cblb's anti- inflammatory function, and their thorough and rigorous testing, will prepare the company for clinical trials with the purpose of improving the lives of people suffering from the consequences of severe sepsis.